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The Future of Discovery at VCU Health

Medicines for All REVOLUTIONIZING THE GLOBAL SUPPLY CHAIN

Spring 2020

Welcome to NEXT Dear Friends, We are excited to share with you the amazing stories of scientific innovation occurring on the MCV Campus at VCU Health in our third issue of NEXT. The impact of these discoveries in treatment, research and education is life-changing for patients in Central Virginia and around the world. From Dr. Gupton’s work developing new pharmaceutical manufacturing practices to establish the Medicines for All Institute, to Dr. Hundley’s exploration of linkages between cancer and heart disease, our faculty investigators are on the cutting edge of medical research. This issue also showcases VCU Health’s expertise in neuroscience. Dr. Cifu is leading a national research consortium studying traumatic brain injuries in military veterans and has received the largest federal grant in VCU’s history. Dr. Zhang is experimenting with new compounds to treat Alzheimer’s disease, and Drs. Costanzo and Coelho have created a prototype device to restore the sense of smell. We also cover nurse researcher Dr. Pretzer-Aboff and how she’s using a grant from The Michael J. Fox Foundation to discover new treatments for Parkinson’s disease. VCU Health is fortunate to garner public and private funding to support this high level of research. Philanthropy is an increasingly important source of support, especially in the early stages of research, before public funding is available. In FY19, the MCV Campus health science schools and college received $179.9 million in new research awards, raising the total MCV Campus sponsored research amount to $683.7 million. We hope you enjoy reading about the groundbreaking work of the extraordinary healthcare professionals at VCU Health and feel inspired to join our community and become a part of the next great discovery.

Margaret Ann Bollmeier

Wyatt S. Beazley IV

PRESIDENT, MCV FOUNDATION

BOARD CHAIR, MCV FOUNDATION

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Small Molecules, Big Ideas Breakthroughs for treating Alzheimerâ€™s disease may rest in novel compounds that stop inflammation responses in the brain.

From One Killer to Another Cardio-oncologists explore links between cancer treatment and heart disease.

The Walking Wounded National research consortium gives hope for healing to veterans and service members with traumatic brain injuries.

Faculty Spotlight Nurse researcher uses vibration to treat Parkinsonâ€™s disease symptoms and improve quality of life.

Scents and Sense Ability Two researchers pioneer technology to restore the sense of smell for millions of people.

COVER STORY

Medicines for All:

Revolutionizing the Global Supply Chain Dr. Frank Gupton (above) is reimagining drug manufacturing to improve health around the world.

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Small Molecules, Big Ideas. CAR T-CELL THERAPY OFFERS HOPE TO CANCER PATIENTS WHEN OTHER TREATMENTS FAIL

By Paul Brockwell Jr.

Breakthroughs for treating Alzheimer’s disease may rest in novel compounds that stop inflammation responses in the brain’s nerve tissues. Shijun Zhang, Ph.D., a professor in the Department of Medicinal Chemistry at the VCU School of Pharmacy, likes to think both big and small. He finds joy and fulfillment in the discovery and engineering of tiny molecules that may lead to an effective treatment for Alzheimer’s disease. More than 5.8 million Americans are living with Alzheimer’s disease, and experts predict that number will soar to nearly 14 million by 2050. The neurodegenerative disease is the sixth leading cause of death in the U.S., and it affects millions more loved ones who often provide care for family members who receive the heartbreaking diagnosis.1 “Alzheimer’s disease is a devastating condition that desperately needs effective treatments to help patients and their caregivers,” Dr. Zhang said. “Our technology may provide a new direction in developing novel compounds to fight this disease.” Emerging research suggests that chronic inflammation may be linked to the buildup of cellular debris that causes neurological dysfunction in Alzheimer’s patients. Armed with that knowledge, Dr. Zhang is researching how to disrupt inflammation responses, which over time lead to degeneration as the disease progresses. By turning off inflammation proteins, Dr. Zhang hopes he can help the body protect the neural pathways that normally are ravaged by the disease. PREPARED FOR THE CHALLENGE Dr. Zhang was trained as a medicinal chemist with a specialty in disorders of the central nervous system. His postdoctoral research focused on designing opioidreceptive molecules that could help reduce abuse and addiction by targeting opioid receptors. The skills he built on that project, he said, translated directly to his work at VCU Health on Alzheimer’s. Currently, he is pursuing two promising lines of research in the development of treatments for Alzheimer’s disease. “In medicinal chemistry, we do a lot of chemical synthesis,” Dr. Zhang said. “If you know how to design, how to synthesize, how to analyze and test compounds, these common skill sets can be applied to any field.” His interest in Alzheimer’s began after engaging with research on the disease that underscored both the severity and scope of the problem. Knowing there was no treatment

or cure inspired him and piqued his interest. His love of teaching brought him to the VCU School of Pharmacy, where he built his lab and research focus around Alzheimer’s disease. Dr. Zhang’s training provided expertise in creating bivalent components, or two linked molecular structures designed to tackle different types of receptors. In his postdoctoral work, he developed structures to address problems with opioid addiction through receptor signaling, and Dr. Zhang saw potential for application to the problem that now captivates his attention. “I want to see whether I can use a similar strategy to tackle the problems involved in Alzheimer’s,” he said. THE TRADITIONAL APPROACH Dr. Zhang’s research to develop treatments for Alzheimer’s disease includes both a targeted drug discovery path and a traditional drug discovery path. In the traditional discovery approach, his team built off research on the neuroprotective properties of melatonin, the sleep hormone, and curcumin, a chemical component of turmeric that gives the spice its bright yellow color. Previous studies have shown that these natural products have properties that decrease neuroinflammation.2-3 One challenge is that the bioavailability, or how much of the substance enters circulation in the body, is poor for curcumin. Knowing that both naturally occurring substances have efficacy at combatting Alzheimer’s disease risk factors provided Dr. Zhang and his team with a starting point for building a new molecule based on the structural components of each. His lab engineered small molecules based on a chemical framework constructed with components from both melatonin and curcumin. Dr. Zhang’s team also tested these novel compounds with the goal of evaluating their effectiveness in cell models, including whether the compounds could cross the blood-brain barrier and if the delivery method of the compounds could ensure enough of the drug was present to have a positive result. The new molecular structure would address various risk factors in the brain with a new mechanism of action. Eventually, they hope to move this research into clinical trials. “We tested these compounds in our Alzheimer’s disease cell model and it’s very promising,” Dr. Zhang said. “When you compare to melatonin or curcumin, it’s better and

This rendering illustrates how amyloid plaques (in orange) disrupt the function of a nerve cell affected by Alzheimer’s disease.

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Progression of Alzheimer’s Disease

Healthy Brain

Mild Alzheimer’s Disease

Severe Alzheimer’s Disease

AN UNFORGIVING DISEASE The progression of Alzheimer’s disease ravages the neural pathways needed for normal brain function. Research into treatments that focus on reducing inflammation responses has shown promise for stopping the cognitive impairments that progressively worsen over time.

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much more neuroprotective.” He and his team have also progressed through various tests to ensure it penetrates the blood-brain barrier. In tests, they also observed improvements in the pathology and in cognition, which was a promising development. Based on earlier studies, his lab continues to craft new analogs of these molecules in order to improve the scaffolding created by combining structural elements of curcumin and melatonin. The new compounds are evaluated based on how protective they are against risk factors for Alzheimer’s disease and whether they can cross the blood-brain barrier to provide enough of the drug needed to be effective. Those factors will help determine which drug candidates move into potential clinical trials. Dr. Zhang’s research was supported in part by funding from the Alzheimer’s and Related Diseases Research Award Fund, which was established by the Virginia General Assembly to stimulate innovative investigations into Alzheimer’s disease, and that support has been critical for helping advance the work to develop and test potential treatments. TARGETING HIS APPROACH Dr. Zhang’s additional research into remedies for Alzheimer’s includes a promising line of work to develop small molecules that function as inhibitors for neuroinflammation. The project initially started with the heart. He and a graduate student working with a cardiovascular lab in the VCU School of Medicine were developing small molecule inhibitors targeted to a specific inflammasome, NLRP3. This NLRP3 protein complex is part of the body’s innate immune response. In many ways, it functions like a home security system. Once the body detects invasions, like a pathogen, the NLRP3 complex assembles and acts as a dispatcher, signaling the body to produce cytokines, such as interleukin 1 beta (IL1ß), which play an important role in signaling cells in various ways during inflammation. Additional research has shown evidence that the NLRP3 protein complex plays a role in the development of neurodegenerative disorders when the immune response becomes out of balance and chronic inflammation occurs.4 The NLRP3 protein complex is important to regulating balance in the inflammatory response, which research literature suggests is a contributing factor in the development of Alzheimer’s disease. The National Institutes of Health awarded Dr. Zhang a grant to explore the creation of inhibitors that could prevent or stop the progression of Alzheimer’s disease by blocking the overactivation of the NLRP3 inflammasome. “When we started this research, we noticed the involvement of the inflammasome, which is critical,

especially as the first barrier in the host system,” Dr. Zhang explained. “We want to see whether we can address what role this NLRP3 protein complex has in the development of Alzheimer’s disease by designing different chemical tools. And on the other side, eventually we want to know whether we can develop some drug candidates from molecules that target the inflammasomes.” With that knowledge, Dr. Zhang and his team soon engaged in repeatedly building and testing small compounds to address the NLRP3 inflammasome complex. In the evolving process, Dr. Zhang and his lab are engineering and testing molecules for their effectiveness at inhibiting the protein. The molecules themselves are also tools, Dr. Zhang said, for better understanding the role the protein complex plays in the development of Alzheimer’s. Their tests confirmed how effective the molecules were by measuring decreases in the byproducts of NLRP3 inflammation. From here, Dr. Zhang’s team ran countless tests of potential compounds to see how they affected the amount of chemical byproduct produced as part of the body’s immune response. Through this screening, they confirmed that the appropriate protein complex was targeted and that their compounds decreased the output of inflammation responses linked to the development of Alzheimer’s disease. They also assessed how the compounds would be absorbed in the body and whether they would successfully penetrate the blood-brain barrier. For Alzheimer’s patients, long-term treatment is expected, so his lab is looking to design a solution that can be orally ingested. Multiple rounds of testing yielded compounds that met Dr. Zhang’s requirements for effectiveness. In particular, the team measured cognitive improvements when using compounds designed to curb the inflammasome complex. Dr. Zhang’s hope is to take compounds from his research into clinical trials. Right now, his team continues to evaluate the pharmacokinetic properties of the compounds and to confirm the toxicology aspects of each compound to ensure the potential treatments are safe for use. “It’s exciting — when you get to testing and see improvements in cognition,” Dr. Zhang said. “This is really promising. We’re confirming our hypothesis and seeing results.” The team has amassed a significant library of compounds and data to support preclinical studies and intends to pursue funding for the work ahead. That support will be critical, Dr. Zhang said, for fueling a discovery process that is ongoing. “As we think about future clinical studies, we may need a better molecule, so we’d go back and continue building and testing candidates for this particular application,” he explained.

Shijun Zhang, Ph.D., a professor of medicinal chemistry in the VCU School of Pharmacy, created a new chemical scaffolding that used structural elements found in curcumin, which gives turmeric its bright yellow color, and the sleep hormone melatonin. Both naturally occurring molecules have been observed to help reduce inflammation linked to Alzheimer’s disease progression. In testing, Dr. Zhang’s novel compounds proved to be more effective than curcumin and melatonin at decreasing neuroinflammation associated with Alzheimer’s disease. Photo: VCU University Marketing

The team is eager and excited to pursue this research, with the goal of advancing toward clinical trials and ultimately, Dr. Zhang hopes, a treatment option that can provide hope for patients and loved ones affected by Alzheimer’s disease. If you would like to be a part of advancing the next breakthrough in discovering treatment options for Alzheimer’s disease, please visit www.MCVFoundation.org. Go directly to the Give Now button and select the “Pharmacy Current Fund” from the dropdown menu and note this research project on the form.

1. According to the Alzheimer’s Association: www. alz.org/alzheimers-dementia/ facts-figures. 2. Sally A. Frautschy and Greg M. Cole. Why pleiotropic interventions are needed for Alzheimer’s disease, Molecular Neurobiology, 41, 392-409. PMID: 20437209 (2010). 3. Seithikurippu R. Pandi-Perumal, Ahmed S. BaHammam, Gregory M. Brown, D. Warren Spence, Vijay K. Bharti, Charanjit Kaur, Rüdiger Hardeland, and Daniel P. Cardinali. Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes, Neurotoxicity Research. 23, 267-300. PMID: 22739839 (2013). 4. J.G. Walsh, Daniel Muruve, and Christopher Power. Inflammasomes in the CNS. Nature Reviews Neuroscience.15, 84-97 PMID: 24399084. (2014).

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Medicines for All REVOLUTIONIZING THE GLOBAL SUPPLY CHAIN By Eric Peters

“Discovery is seeing what everybody else has seen, and thinking what nobody else has thought.” Albert Szent-Györgyi, Nobel-Prize winning co-founder of the National Foundation for Cancer Research

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The supply chain for prescription drugs in the U.S. and around the world is far more vulnerable than many people would like to think. According to the FDA, more than 100 drugs are in short supply in the U.S. alone right now.1 These are prescription drugs that are lifesaving, life-sustaining or used in the prevention or treatment of debilitating diseases and conditions. Furthermore, approximately 80% of all medications consumed in the U.S. are produced in India or China,2 which drastically reduces our ability to control drug supplies and causes considerable supply chain risks. The World Health Organization and others have said this is not just a U.S. problem, but a global one, and the need for drugs is growing. Worldwide, there are more than 37 million people infected with HIV,3 219 million malaria cases4 and 10 million tuberculosis cases.5 These issues â€” domestic and international drug shortages and hundreds of millions facing life-threatening diseases â€” are enormous and complex. Staring down one, let alone all of them, is daunting to say the least. But the mantra of a lab in Richmond at Virginia Commonwealth University perfectly summarizes the way its students, faculty and staff have begun to approach these global challenges.

Medicines for All: Nevirapine Results Changes to nevirapine production processes that Medicines for All has identified and implemented have improved: Nevirapine Isolated Yield 100%

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The isolated yield, or the amount of product obtained from the chemical reaction after purification, improved from 56% to 94%. This means that the efficiency of the process has drastically improved, and manufacturers can produce more product.

Nevirapine Process Mass Intensity (PMI)

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Commercial Process

M4All Process

The PMI, or total mass of all materials used to produce 1 kilogram of final product, improved from 56 kilograms to 4 kilograms. This drastic reduction in the amount of materials it takes to produce the final product has reduced costs and environmental impact.

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of all medications consumed in the U.S. are produced in India or China.

Their creed, “Discovery is seeing what everybody else has seen, and thinking what nobody else has thought,” is an Albert Szent-Györgyi quote often shared by Frank Gupton, Ph.D., the Floyd D. Gottwald Professor and Chair of the Department of Chemical and Life Science Engineering in the VCU College of Engineering. Dr. Gupton, a former pharmaceutical industry executive, leads VCU’s Medicines for All Institute. The institute examines commercial drug manufacturing processes to find ways to substitute lower-cost raw materials, simplify operations and increase yields. It then transfers its findings to manufacturers and suppliers that can reduce consumer prices and establish production closer to patients, where it previously wasn’t economical to do so. This approach and the promising findings it has produced have caught the eye of the Bill and Melinda Gates Foundation, earning Medicines for All nearly $40 million in funding since 2014. One of the institute’s first projects examined nevirapine, a widely prescribed treatment for HIV that is on the World Health Organization List of Essential Medicines. Medicines

for All pinpointed inefficient chemical conditions and production processes related to the drug, then streamlined routes to the materials that come together to create its active pharmaceutical ingredient (API). The team’s changes to nevirapine’s production improved isolated yield, or the amount of product obtained from the chemical reaction after purification, from 56% to 94%. The changes also improved the process mass intensity (PMI) value, or the total mass of all materials used to produce 1 kilogram of final product, from 56 kilograms to 4 kilograms. Medicines for All researchers shared the details of their streamlined nevirapine process with the Clinton Health Access Initiative (CHAI), which quickly integrated the new process into its supply chain network in 2015. So far, savings on the cost of goods used to produce the drug have been close to 40%. This substantial cost savings enables agencies that procure and distribute HIV drugs, such as USAID, Unitaid and the South African government, to purchase more medication for the same amount of money. The extra medication then reaches people who need it in order to lead

The substantial cost savings that Medicines for All has created have enabled global relief agencies to procure and distribute more HIV medications to people who need them in order to lead healthier lives or to prevent HIV transmission from mothers to their children, which is the way 90% of new HIV infections are transmitted to children.

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Improving the Process The Medicines for All Institute reevaluates the decades-old processes that are being used to produce global health drugs by substituting lower-cost materials, simplifying operations, reducing waste and increasing yields. These changes dramatically reduce selling prices and improve access and supply chains around the world.

Substitute lower-cost raw materials

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healthier lives or prevent HIV transmission from mothers to their children, which is the way 90% of new HIV infections are transmitted to children globally. CHAI’s Prevention of Mother-to-Child Transmission program, for example, supports HIV-positive mothers from pregnancy and delivery through breastfeeding and into long-term care. Anita Deshpande, who previously worked for CHAI, is the director of market engagement at the Medicines for All Institute. “I have spent time in HIV clinics across Africa, in India and in the Caribbean,” she said. “It has been clear in all of these places that securing the supply chain for these lifesaving medications will enhance the lives of all patients, including mothers, young men and adolescents. These are the drugs that allow patients to live fairly normal lives. Making sure everybody has access to them gives people an opportunity to raise their children and see those children live HIV-free lives.” Dr. Gupton and his team have only published their nevirapine results, but they are working through manuscripts on five other medicines. In all the cases, they’re finding what Dr. Gupton calls “low-hanging fruit,” similar to what they found in the nevirapine process that is allowing them to reduce both cost and the amount of materials needed for production. These changes will lead to an estimated consumer price reduction of approximately 10% on each therapy, bringing the potential savings across several HIV regimens around the globe to almost $90 million annually. “The medications that Medicines for All is working on are the most used HIV drugs in the world,” Deshpande said. “Securing their supply chain and improving their affordability will ensure more patients have access to these World Health Organization-preferred treatments.”

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Novel Chemistry

Simplify operations

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IDENTIFYING OPPORTUNITIES FOR CHANGE How did this “low-hanging fruit” grow, and why has no one come along to pluck it from the branch until now? Synthetic processes to develop new APIs often evolve with limited regard for commercial viability and efficiency. In many cases, these early processes help define the final commercial production processes of drugs because that is the fastest route to market. In the eventual drug price for consumers, APIs represent only about 10% of the cost, while research and development represent about 75%. Therefore, in the 20 years that follow, pharmaceutical companies put their resources into research and development of new drugs rather than fine-tuning the processes for their existing APIs. Then, after a couple of decades, those API processes are frequently carried forward into the production of generic versions of drugs without ever being questioned. It is here that the major opportunities and “low-hanging fruit” lie, because the economics completely flip in the generic marketplace. The APIs in generic drugs now represent 50% to 70% of the selling price, so if a group could reevaluate the decades-old processes that are being used to produce the APIs, it could dramatically reduce the selling price. “That’s exactly what we do here,” Dr. Gupton said. “We go in and look at drugs with a new set of eyes and some new chemistry tools, and we make them cheaper and more accessible.” Another way inefficient drug production has perpetuated is through a generally accepted method known as batch production. Batch production involves making drugs in single clusters, which is a practice Dr. Gupton’s team is working on moving away from in favor of continuous manufacturing, or flow chemistry. They first completed

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their nevirapine work using a batch process, but were able to translate that drug’s process, and the processes of others, into a continuous format. Dr. Gupton uses a metaphor about spaghetti to explain the importance of a continuous method over a batch method. The sauce is made in a batch — everything goes into the pot, cooks and then is taken out. Not only is there a beginning and an end to this process, which slows it down, it also means that each batch is going to be slightly different from the previous one. Pasta, on the other hand, can be continuous in that ingredients are going in one end of the pasta maker and coming out the other, uninterrupted. Each noodle is the same. “Continuous processing technology is not anything new, it’s just new to the pharmaceutical industry,” Dr. Gupton said. “The FDA is really interested in implementing this for the simple reason that it creates a process that consistently produces materials that meet specifications.” The continuous format also creates a tremendous advantage from a manufacturing perspective, which is leading to opportunities to improve domestic drug supplies. “Right now, nearly all of our drugs are being produced in India and China,” Dr. Gupton said. “One of the reasons people go to China is because of their labor costs. If you were to be able to do these processes continuously, that is, in an automated fashion, the labor requirement would go down and make it more competitive to bring these processes back to the United States.” In bringing these processes back to the U.S., supply chains — not just for HIV drugs, but for many others that are currently produced outside of the U.S. — can be established and strengthened domestically for the foreseeable future.

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ENVIRONMENTAL IMPACT In addition to lowering costs and access to drugs, the fresh perspective that Medicines for All is applying is reducing the environmental impact of drug making. Traditional commercial API processes produce between 50 and 200 kilograms of waste per single kilogram of final product.6 Through its previous production processes, nevirapine produced about 60 kilograms of waste per kilogram of final product, but Dr. Gupton’s team cut that waste to just 4 kilograms. “That is unheard of in a pharmaceutical product,” Dr. Gupton said. “And since we hit that number with nevirapine, it’s the benchmark for every new process we develop moving forward.” This dramatic reduction in waste generation was a key success factor in getting these new processes implemented at existing manufacturing facilities. China, for example, has been aggressively pursuing waste reduction related to the pharmaceutical industry and has shut down facilities that generate significant quantities. By reducing the amount of waste generated in these processes, the Medicines for All approach has enabled companies to adhere to the new regulations in the country and helped to get the new process for nevirapine implemented more quickly around the world. Several industry groups have recognized the impact Medicines for All is making on the environment, and in 2018 the American Chemical Society presented Dr. Gupton and his colleague Tyler McQuade, Ph.D., professor of chemical engineering at VCU, with the Award for Affordable Green Chemistry and the Green Chemistry Challenge Award, which recognizes corporations and institutions for developing new chemical processes or products that reduce waste and hazardous chemicals. The team was cited for

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Partnerships on the MCV Campus MASSEY CANCER CENTER The NCI-designated VCU Massey Cancer Center is in the top 4% of cancer centers nationally. It produces groundbreaking research, training and the best possible care. One barrier to the center moving into an even more elite designation is its access, for research purposes, to the absolute newest drugs that are still in early trial phases. “The pharmaceutical companies that are developing these drugs want to control the use of them in both preclinical research and clinical trials, which is understandable,” Dr. Gupton said. “But when Massey mentioned this challenge to me, I said, ‘They publish the structures of the compounds, so there’s no reason why we can’t make them for you.’”

The Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Amendments, allows organizations to produce a drug that is under patent if that organization isn’t planning to sell it. “So, we set up a lab here, and we’ve been making the drugs for Massey for a little less than a year,” Dr. Gupton said. “The partnership with Dr. Gupton’s Molecules for Medicine program opened a whole new avenue for Massey Cancer Center investigators to move laboratory discoveries forward to clinical trials,” said Gordon Ginder, M.D., former director of VCU Massey Cancer Center and Lipman Chair in Oncology. “We believe that growing this partnership will accelerate translational research, and with it, our ability to bring innovative new treatments to patients with cancer.”

SCHOOL OF PHARMACY In 2019, the State Council of Higher Education for Virginia approved the nation’s first Ph.D. program in pharmaceutical engineering. The doctoral program, a collaboration between VCU’s School of Pharmacy and College of Engineering, will focus on research and training students in areas of drug product development, such as continuous manufacturing and drug-containing nanomaterials. “We have a lot of people from the pharmaceutical industry working in the space with Medicines for All, and other researchers throughout the College of Engineering who are working with various drugs and therapies, so we can coalesce all of that activity with the School of Pharmacy to create something meaningful and unique,” Dr. Gupton said. “People have been compartmentalized in their skill sets in this industry. You have organic chemists who are focused on the synthesis and drug discovery part. Then someone must formulate the product. What if you had somebody who understood what those requirements were downstream who could interface between drug discovery and drug development? That’s where we think the sweet spot is for this degree.” “VCU has always prepared professionals and scientists for the healthcare needs of the future, and this new collaborative Ph.D. program supports that mission,” said Joseph T. DiPiro, Pharm.D., dean of the VCU School of Pharmacy and the Archie O. McCalley Chair. “It will

bring together students and researchers from the two disciplines to solve problems that will have visible and important effects on health.” It is through this partnership that the university is teaching students, hopefully a new generation of pharmaceutical industry experts, to take Dr. Gupton’s adopted mantra about looking at familiar things with a fresh perspective into the rest of the pharmaceutical and global health world. Barbara D. Boyan, Ph.D., the Alice T. and William H. Goodwin Jr. Dean of the College of Engineering, said, “With the creation of the pharmaceutical engineering Ph.D. program, VCU will be a national leader in the education of the pharmaceutical workforce of today and innovators leading future developments. The program will address the growing need for a new generation of researchers trained in cross-disciplinary and interdisciplinary science who recognize the need for a team-based approach to solving challenges related to the design and manufacturing of pharmaceutical products.” “Our charter here is to train students to think differently — to use common sense,” Dr. Gupton said. “The question is how do we change the industry culture to achieve those objectives both in the training of our academicians here and when they go into the world to start implementing these key principles in the marketplace.”

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Cheryl Peck, Ph.D., a postdoctoral research associate at the Medicines for All Institute, consults with Frank Gupton, Ph.D., at their lab in Richmond. Photo: Kevin Schindler

outstanding success in developing a sustainable and efficient synthesis of nevirapine, resulting in reduced costs and improved access to HIV treatment.

well-equipped. The Gates Foundation has enabled us to build up this infrastructure, allowing us to look at these other drugs much more cost effectively.”

WHAT’S NEXT? Next year, Dr. Gupton and his team will begin working on tuberculosis and malaria drugs. “It made perfect sense to do it this way,” Dr. Gupton said. “We started with these high-volume HIV drugs. If you have a good return on investment with them, that allows you to baseload your cost here at the institute so you can now work on TB and malaria. The research on HIV drugs basically paid startup costs for moving into the new diseases. We are extremely

If you would like to help strengthen Dr. Gupton’s

1. U.S. Food and Drug Administration (2019). Drug Shortages webpage. www.fda. gov/drugs/drug-safety-and-availability/drug-shortages.

4. World Health Organization (2019). Malaria Fact Sheet. www.who.int/newsroom/fact-sheets/detail/malaria.

2. B. Frank Gupton (2019). Increasing Access to Global Healthcare: The Medicines for All Institute. Presentation to the MCVF Board of Trustees.

5. World Health Organization (2019). Tuberculosis Fact Sheet. www.who.int/newsroom/fact-sheets/detail/tuberculosis.

3. U.S. Department of Health and Human Services (2019). Global HIV/AIDS Overview. www.hiv.gov/federal-response/pepfar-global-aids/global-hiv-aidsoverview.

6. Roger Sheldon (2010). Introduction to Green Chemistry, Organic Synthesis and Pharmaceuticals. In Green Chemistry in the Pharmaceutical Industry (eds P. J. Dunn, A. S. Wells and M. T. Williams). doi:10.1002/9783527629688.ch1.

partnerships across the MCV Campus, please consider reaching out to gift officers who can help you begin the process. To learn more about the School of Pharmacy, contact Louie Correa, senior director of development, at 804-828-3016 or lacorrea@vcu.edu. To learn more about Massey Cancer Center, contact Martha Quinn, executive director of development, at 804-827-0652 or mquinn3@vcu.edu.

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From One

Killer to Another Exploring the Link Between Cancer Treatment and Heart Disease By Eric Peters

After battling and beating the second leading killer on Earth, what could be more demoralizing and daunting than going right into a fight with the leading killer on Earth? This is the reality for a growing number of people who survive cancer — the No. 2 cause of death on the planet — because, as a result of their treatment, many face cardiovascular disease — the No. 1 cause of death on the planet. As cancer therapies become much more successful, survivors are experiencing this series of events due in part to traditional chemotherapy, radiation therapy, immunotherapy, transplantation therapy and endocrine modification therapies having adverse effects on the heart and the blood vessels. One remarkable example that illustrates this phenomenon has to do with women who are battling breast cancer. Studies

now indicate that the leading cause of death among those women is actually not breast cancer. It is heart disease. To address cardiovascular conditions in those being treated for cancer, a relatively new specialty — cardiooncology — has emerged to investigate and preserve heart health among cancer patients. A top researcher in the field is Greg Hundley, M.D., who graduated from the VCU School of Medicine in 1988, went on to the University of Texas Southwestern Medical Center and Wake Forest Baptist Medical Center, then returned to the MCV Campus in 2018 to serve as director of the Pauley Heart Center. IMAGING IN RESEARCH Dr. Hundley uses magnetic resonance imaging (MRI) in the clinic and in his research. This noninvasive form of imaging, which doesn’t require catheters, surgical

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Greg Hundley, M.D., director of the Pauley Heart Center, discusses the advanced imaging capabilities of the MRI system in VCU Health’s Cardiac Imaging Suite, which supports personalized cardiovascular evaluation, diagnosis and treatment for both Pauley Heart Center and Massey Cancer Center patients. Dr. Hundley, a Richmond native and VCU School of Medicine alumnus, is recognized for studying the impact of chemotherapy and radiation therapy on heart health and advancing treatment options for patients in need of cardiovascular and oncology care. Photo: Kevin Morley, VCU University Marketing

procedures or ionizing radiation (X-rays), enables his team to monitor patients frequently or over long periods of time as they receive cancer treatment. This MRI method also enables investigators and clinicians to evaluate the heart and blood vessels in a single examination. Dr. Hundley was the first in the world to demonstrate that MRI stress testing can identify those at risk of heart attack. “When you have a disease process that is complicated to understand, you need a tool that can look at many different aspects of that disease process in a single setting,” Dr. Hundley said. “We’ve used MRI to identify heart disease in those with and receiving treatment for cancer.” In addition, a unique feature of the imaging capabilities at VCU Health is the ability to acquire images while patients are lying still and when they are under physiological stress. At the Pauley Heart Center Cardiac Imaging Suite on the MCV Campus, Dr. Hundley’s team can monitor patients after they have been running on

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a treadmill or while they’re pedaling a stationary bicycle inside a scanner. Gathering images under these conditions provides investigative teams and clinicians a unique opportunity to better understand disease processes that impact abilities to carry out activities of daily living. “An analogy is when your car has a problem,” Dr. Hundley said. “You don’t take it to a service station and everyone stares at it while it’s off; that would be your condition at rest. You start the car and you push on the accelerator. It is when you start to do things — you grocery shop, you walk down the street or up stairs in a building — that you can experience symptomatology of cardiovascular disease.” Dr. Hundley is using this technology to help measure outcomes in four ongoing or recently completed studies, described on the following pages, focusing on cardiovascular diseases that are accelerated or newly developed as a result of having cancer or receiving treatment for cancer.

DETECT Dr. Hundley’s Detect study was funded by the NIH and ended last fall. It involved women with breast cancer and both women and men with lymphoma, exploring whether cardiovascular magnetic resonance imaging (CMR) could identify subclinical cardiac disease in patients receiving potentially cardiotoxic cancer treatment regimens. Subclinical disease is not yet detectable by the usual tests, but diagnosis in this stage can be critical for initiation of early treatment to improve quality of life and survival. The study found that utilizing contemporary CMR to accurately define cardiac anatomy, function and tissue characteristics may represent a critical tool to assess patients who have undergone cancer treatment.1 “To reduce the incidence of cardiovascular events among cancer survivors, there is increasing interest to identify subclinical cardiac abnormalities that portend future cardiovascular events,” Dr. Hundley and his team wrote. “In so doing, one could identify those suitable for cardiovascular interventions to prevent these future untoward cardiovascular events.”2 PREVENT Prevent is a 24-site placebo-controlled, double-blind clinical trial funded by both the Heart, Lung and Blood Institute and the National Cancer Institute at the NIH. It is examining whether receipt of a statin during breast cancer treatment reduces heart and vascular dysfunction. Statin therapies are used today to lower cholesterol, but they also have pleiotropic effects, meaning they reduce systemic inflammation, a condition that contributes to heart dysfunction after cancer treatment. Participants in the two-year study are those with lymphoma or breast cancer who take anthracycline-based chemotherapy, and the advanced MRI technology at VCU Health is one of the ways outcomes are being measured. Because the study is a double-blind clinical trial, neither the trial investigators nor the patients will know who is taking the placebo until the study has been completed. What investigators can do, though, is look at the data in aggregate to see both placebo and non-placebo groups as a single unidentified sample of 279 patients. “What we’re seeing is that some patients have more of a decline in heart function, some patients have no decline, and a few patients have

an increase,” Dr. Hundley said. “So, the question is, when all of that is unblinded in the next six months, did the statin ingestion promote the preservation of the heart performance?” Many secondary outcomes are being investigated in this study, including cognition, because some chemotherapies are associated with cognitive decline while statins have been shown to both reduce and preserve cognition. The team will also look at vascular function and the occurrence of heart events like heart attacks and strokes. UPBEAT Another problem for women who are treated for cancer relates to the development of fatigue, which occurs in about one-third of women undergoing treatment. In one-third of that one-third, women don’t go back to work, and they may experience unwanted changes in their family units, including divorce, as a result. “It’s unrelenting, it never goes away,” Dr. Hundley said. “And we don’t understand why that fatigue is developing. What better than to perform a noninvasive imaging modality that looks at multiple aspects of your body — your heart function, your blood vessel function, your body composition — to try to gain some understanding about the precipitating factors of that fatigue?” A research participant pedals a stationary bicycle inside an MRI scanner, which plays a major role in cardio-oncology research led by Greg Hundley, M.D., director of the Pauley Heart Center. Gathering images under these conditions provides investigative teams and clinicians a unique opportunity to better understand disease processes that impact abilities to carry out activities of daily living. Photos: Eric Peters

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“We want to avoid a situation where we trade one bad disease — breast cancer — for another, which is unrelenting fatigue related to the development of heart failure.” The UPBEAT study also evaluates emotional state, social situation, environmental stress, perceptions of those stressors and cognition. Funded by the NIH through the National Cancer Institute, it is a longitudinal cohort study, or one that follows a group of patients with similar experiences or diagnoses over time. It is another national multicenter study with 24 centers participating. Research participants undergo exercise testing, blood testing, genetic testing and the advanced MRI imaging. “We want to avoid a situation where we trade one bad disease — breast cancer — for another, which is unrelenting fatigue related to the development of heart failure,” Dr. Hundley said. “You don’t want a woman who is 42, has two young children and undergoes cancer treatment to later not be able to participate in the activities of those children and all the things they need.” There is also a disparities component to UPBEAT. African American women experience fatigue, heart failure and adverse heart conditions more frequently than those of other races or ethnicities, so there are specific questions in the study that are related to understanding these harmful comorbidities. PALS The Physical Activity in Lymphoma Study, or PALS, is Dr. Hundley’s newest study, and is the project in which he is approaching cardio-oncology with the most unique lens. As care providers and researchers learn how adverse heart conditions develop during cancer treatment, they’re looking at many ways to approach the issue. The Prevent study, for example, is investigating a statin therapy, and studies around the world are looking at other heart failure therapies in the form of administering pills. PALS is quite different. “We’ve noticed in cancer survivors, after their treatment, if we can get them exercising, they tend to do better,” Dr. Hundley said. “So, one thing we might consider, which is a total paradigm shift in medicine, is to actually get people to start exercising during their cancer treatment.” Dr. Hundley sees a parallel in this potential shift with one that occurred in a different clinical scenario over the

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Greg Hundley, M.D., director of the Pauley Heart Center past half century. “Forty to 50 years ago, when a patient experienced a heart attack, our common thinking was to keep them at bedrest for a month to let them recover,” he said. “Today the paradigm has changed dramatically. We invoke cardiovascular rehabilitation — riding bicycles, walking around tracks under supervision — almost immediately after a heart attack. If you have a heart attack today, provided you don’t have other issues ongoing, the following day we get you up in a chair. On day two, we walk you in the hall. On day three, you’re in a cardiac rehabilitation situation where you’re performing supervised exercise.” With these things in mind — evidence about the benefits of exercise following cancer treatment and decades of lessons learned from heart attack recovery — the team, led by Dr. Hundley, is examining whether it is beneficial to walk, exercise and strength train in the days between chemotherapy infusions. “This is no easy task for patients, because cancer treatment is horrible,” Dr. Hundley said. “You lie there in a chair and receive IV therapeutics that are toxic. They make you feel terrible, you experience nausea, vomiting and your hair falls out. About the last thing you want to do is move. There are many aches and pains related to cancer treatment.” PALS will use advanced MRI to measure exercise capacity, questionnaires to evaluate quality of life and fatigue, studies to measure cognitive ability, and blood tests to monitor inflammatory mediators that are associated with adverse cardiovascular effects. PALS is a multicenter study that began this spring and has five more years to enroll patients. It is a unique, communitywide partnership in Richmond because VCU Health is partnering with Sheltering Arms rehabilitation centers to deliver interventions. “Our partnership with Sheltering Arms is important in providing facilities where patients who are immunocompromised can go and exercise without picking up an infection from someone else who has touched the equipment,” Dr. Hundley said. “We have to do these studies in cardiac rehabilitation facilities.” These types of partnerships, both within VCU Health and in the wider community, are reasons Dr. Hundley sees

VCU Health and the MCV Campus as such an impactful place to conduct research and deliver care. “Here at VCU, we’re trying to advance the care of everyone,” he said. “We don’t have the more traditional silos of operation; we’re integrating with a lot of different groups that freely exchange information. VCU Health also has enormous advantages related to technical capabilities. The MRI scanner we’ve discussed, for example, is one in which you can ride a bicycle and gather images simultaneously. There aren’t many places on Earth that can do that. “Applying this technology and interdisciplinary approach, you have Massey and Pauley working together and leveraging the talents of not just a health system,

but an entire university to address why we’re facing these problems and what solutions exist.” If you are interested in helping the Pauley Heart Center continue to utilize the best resources and technology available, which enable preeminent patient care, research and education here in Central Virginia, please contact Carrie Mills, senior major gifts officer at VCU Health, at carrie.r.mills@vcuhealth.org or 804-828-0423.

1, 2 Amitabh Parashar, W. Gregory Hundley. The Role of Cardiovascular Magnetic Resonance for Surveillance of Cardiac Performance upon Receipt of Potentially Cardiotoxic Cancer Therapeutics. Curr Cardiol Rep, 2018;20(12):142. doi:10.1007/s11886-018-1075-7. PMID: 30367282.

A Family Dedicated to Heart Health Greg Hundley, M.D., graduated from VCU School of Medicine in 1988 and returned in 2018 to serve as director of the VCU Health Pauley Heart Center. His return to the MCV Campus, and the opening of the Cardiac Imaging Suite where he conducts research, would not have been possible without the generosity of Stan and Dorothy Pauley and the Pauley Family Foundation. In addition to making a generous donation to name the Pauley Heart Center in 2006 and another multimillion-dollar gift in 2013, the family supported Dr. Hundley’s recruitment and funded the suite’s 3T MRI scanner, which is one of the most advanced MRI systems available in the world. After the 2006 and 2013 gifts, Kenneth Ellenbogen, M.D., the Martha M. and Harold W. Kimmerling, M.D., Chair of

Cardiology, said the Pauley family had transformed VCU Health into a first-tier heart center by helping the health system devote resources toward renovating and improving research and attracting new faculty in cardiology to enable care of the sickest and most complex patients from all over the region. Stan Pauley is one of those patients. “This is a project that is near and dear to my heart,” he said in 2013. “The care these healthcare professionals provide is so genuine and moving that it is an honor to contribute to research that will enable them to learn even more about heart disease.” This February, Stan, Dorothy and the Pauley Family Foundation once again made an investment to fortify VCU Health as a national leader in cardiac care. The foundation donated $5 million to the Pauley Heart Center that will provide resources to research, diagnose and treat atrial fibrillation and ventricular tachycardia, which are two types of irregular heart rhythms. These rhythm disturbances increase mortality, reduce quality of life and limit a person’s ability to perform everyday activities. As the population ages, atrial fibrillation is increasingly common. “With the growing number of patients worldwide who develop atrial fibrillation, the gift from the Pauley family will help us work to develop new and more precise methods of mapping the heart to better identify and destroy the circuits causing atrial fibrillation,” Dr. Ellenbogen said. Stan Pauley (left) greets Greg Hundley, M.D., director of the Pauley Heart Center, before the ribbon cutting at VCU Health’s new Cardiac Imaging Suite. Kathy Pauley Hickok and Gene Hickok are also pictured as they await the ribbon cutting. In addition to making a generous donation to name the Pauley Heart Center in 2006, the Pauley Family Foundation supported Dr. Hundley’s recruitment and funded a portion of the suite’s equipment. Photo: Kevin Morley, VCU University Marketing

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THE WALKING WOUNDED Healing the Unseen Injuries of Our Military Heroes By Alex Henley

Imagine waking up after being knocked out by an IED. You’re on the ground, face in the dirt, and not sure what just happened. Despite being groggy and confused, you must act quickly because you’re in enemy territory. After a quick assessment, you find yourself one of the lucky ones — there’s no external bleeding or other visible injuries. There’s a piercing pain in your head, your ears are ringing, and you can’t get your eyes to focus, but you force yourself to stumble around and check on the rest of your unit so you can all move to safety. This is what countless military heroes have faced in the course of battle, some of them many times. It’s what medical professionals call a mild traumatic brain injury (mTBI), commonly known as a concussion. As the weapons of warfare have changed, with blast injuries on the rise, military personnel have returned from battle with different types of injuries. Since 2000, the U.S. Department of Defense reported more than 383,947 military personnel have sustained a traumatic brain injury, and 82.3% of these are mild.1 Actual numbers are likely much higher as many mTBIs go unreported. “No one stops in the middle of a battle and gets assessed for a concussion,” said David Cifu, M.D., chair and professor of the VCU School of Medicine’s Department of Physical Medicine and Rehabilitation and senior traumatic brain injury specialist for the U.S. Department of Veterans Affairs. “Service members want to and need to keep fighting.”

WHAT IS A CONCUSSION? A concussion is the mildest form of a traumatic brain injury usually resulting in no loss of consciousness or, rarely, in a brief loss of consciousness under 30 minutes. It involves a disruption in the normal function of the brain caused by a sudden force, bump or blow to the head that forces the brain to rapidly accelerate and then decelerate. “The brain is made up of white and gray matter,” Dr. Cifu explained. “If you imagine a Jell-O fruit dessert, the white part of the brain is like the fruit. It’s fairly firm in consistency, is located deep inside the brain and is the communication system — it connects the different parts of the brain to the spinal cord. The gray matter does the thinking, creates the actions and generates our feelings. Its consistency is soft and wobbly like Jell-O and it is on the outside, surrounding the white matter. “Where the gray and white matter come together offers a significant difference in tissue density, just like the difference between the Jell-O and the fruit (‘the gray-white junction’). If you’ve ever shaken up Jell-O, you’ve seen the Jell-O move or wobble, while the fruit sits there, and if you look closely you’ll see the separations and air bubbles where the Jell-O and fruit meet (‘the Jell-O-fruit junction’). That’s sort of how a concussion occurs — the force causes rapid bursts of movement and the differences in tissue density stretch the brain tissue beyond its capacity, causing the gray and white matter to separate, tear and become

Two MRI scans show a healthy brain on the left and a brain that has suffered an mTBI on the right. The arrows on the right point to areas where the force of the concussion caused the white matter in the brain to twist and tear beyond its ability to stretch. While it’s helpful for physicians to confirm a traumatic brain injury with an MRI, many concussions do not show up on scans and must be diagnosed by a patient’s symptoms. Photos: Courtesy of VCU Health and Dr. David Cifu

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“No one stops in the middle of a battle and gets assessed for a concussion. Service members want to and need to keep fighting.” David Cifu, M.D., chair and professor of the VCU School of Medicine’s Department of Physical Medicine and Rehabilitation

dysfunctional. If it tears a lot, it bleeds and you have a more significant injury, but the majority of the time it’s either just small tears or simply overstretching that temporarily alters the brain’s abilities and leaves the person feeling confused and disoriented.” The vast majority of people who have a concussion make a full functional recovery, often within days or weeks. However, if a person has had multiple concussions, gets tears in just the wrong locations or has had a more severe injury that is undiagnosed or untreated, the person may experience ongoing symptoms, such as headaches, dizziness, irritability, sleep disruptions, memory issues, anxiety, and sensitivities to light and sound, which are collectively called “persistent, post-concussion symptoms.”

CHRONIC EFFECTS OF NEUROTRAUMA CONSORTIUM (CENC) As U.S. veterans began returning home from the wars in Iraq and Afghanistan and reporting post-concussion symptoms, research into traumatic brain injuries increased. In 2013, the Departments of Defense and Veterans Affairs awarded Virginia Commonwealth University a $62.2 million grant to lead the Chronic Effects of Neurotrauma Consortium (CENC), making it the largest grant in VCU’s history. Dr. Cifu was named the principal investigator for CENC, a five-year study that brought together more than 70 of the top brain researchers in the country across 30 universities, 15 Veterans Affairs Medical Centers and 12 military treatment facilities.

CENC Accomplishments • CENC researchers successfully recruited more than 2,300 veterans and service members, who served in the wars in Afghanistan and Iraq, as active study participants. These post-9/11 individuals, including those with mild traumatic brain injury (most with multiple concussions), PTSD, chronic pain, depression and other symptoms, are now available to participate in a series of planned treatment studies. More than 1,700 of these individuals (and another 1,300+) are also continuing as participants in an ongoing longitudinal study that allows researchers to follow their health outcomes over the course of their lives. • CENC developed a standardized mild traumatic brain injury research assessment protocol. This is particularly important because concussions can be challenging to diagnose after the fact and hard to characterize — in fact, they show no abnormalities on MRIs or other

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imaging tools in more than two-thirds of cases. CENC researchers have created the gold-standard, diagnostic clinical interview and overall approach to assessing and following these individuals that includes learning about the patient’s symptoms and blast exposure event(s), and performing balance testing, blood biomarker and other tests. • CENC combined nine military, veteran and federal databases into a single, searchable mega-database with the health, medication, benefits and administrative information from more than 2 million service members and veterans, which will allow researchers to complete epidemiologic studies using big data analyses. • CENC researchers published more than 70 peerreviewed papers, completed 11 research studies and participated in more than 150 lectures internationally.

As faculty members of the VCU School of Medicine’s Department of Physical Medicine and Rehabilitation, Dr. David Cifu and Dr. Ronald Seel have helped veterans and service members heal for decades. Now, they are partnering to make the CENC research understandable and accessible to everyone. Photo: Kevin Schindler

“VCU has a long history as a leader in traumatic brain research,” said Ronald Seel, Ph.D., executive director of the VCU Center for Rehabilitation Science and Engineering. “The roots of our Department of Physical Medicine and Rehabilitation go back more than 150 years to the Civil War. In addition to our capabilities as an academic health center, we’re proud to serve veterans through a partnership with the Hunter Holmes McGuire VA Medical Center in Richmond. David Cifu has a national reputation as an energetic leader that can make things happen. Those were all contributing factors in VCU being named the coordinating center and receiving this grant.” Beginning in October 2013, CENC researchers launched multiple studies with service members and veterans to better understand both the immediate and longer-term issues associated with combat-related blast concussions to develop better treatment protocols. The accomplishments made by CENC researchers since 2013 have been substantial. While it is impossible to cover the entirety of their work, a few key accomplishments and findings are highlighted below and on page 22. CENC KEY RESEARCH FINDINGS The good news is that more than two-thirds of the post-9/11 service members and veterans in the ongoing longitudinal study (1,700 participants) who have experienced one or

more combat-related traumatic brain injuries are doing well. They are high-functioning members of society who are employed and active with their families and in their communities. While they may have some issues with headaches or other symptoms, they are receiving treatment and able to manage these symptoms and live full lives. A little less than one-third of this population is having more significant symptoms that are not allowing them to return to the full function they had before military service. A positive takeaway is that this group is following up with their physicians and seeking the care that they need. In more good news, none of the post-9/11 longitudinal study participants have shown signs of dementia or Parkinson’s disease, and there have been no suicides. These study participants are, on average, 11 years out from their last combat-related traumatic brain injury and more than 20 years from their first one. One CENC study involved 322 post-9/11 veterans and service members and looked at whether mild traumatic brain injury was related to ongoing difficulties with balance. Researchers used their intake interviews to categorize participants into groups of those with no mTBI, 1-2 mTBIs, and more than 3 mTBIs. Results showed no difference in balance between participants with no mTBI and 1-2 MTBIs, but they did find that service members who suffered 3 or more mTBIs had poorer balance, with pain as a contributing

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Researchers are investigating whether the presence of certain proteins in the blood can be used as biomarkers to indicate whether a combat-related concussion has affected a person’s brain health. Photo: Julia Rendleman, VCU University Marketing

factor.2 This helps alert physicians to focus on possible risks for dizziness and balance issues when treating a veteran or service member who has multiple mTBIs. Another CENC study used the mega-database of 2 million veterans and service members to examine the relationship between traumatic brain injury and Parkinson’s disease. Researchers used the records of 325,870 veterans, with an average age of 48, some of whom had 1 or more TBI and others who never experienced a TBI. The results showed that patients with a history of any severity of TBI had twice the rate of eventually developing Parkinson’s disease compared to those with no history of TBI. Those who had only sustained a prior mild TBI had a nearly 1.5 times higher risk than those without any TBI history. The overall incidence of developing Parkinson’s disease is quite small for all veterans, less than one in 100; however, the results illustrate both the strength of “big data” research and that there is a significantly increased risk for developing Parkinson’s disease in service members who have suffered a TBI.3 Another big data study examined the relationship between mild traumatic brain injury and dementia. Investigators compared the records of 357,588 veterans, average age of 49 years old, half of whom had experienced 1 or more TBI and half who had no history of TBI. Veterans with any TBI history developed dementia at a rate of 6.1%, compared to only 2.6% of veterans with no TBI history — a nearly 2.5 times increase in incidence. After adjusting for factors that could influence dementia rates, the chance of developing dementia was 2.4 times greater for veterans who had experienced a mild TBI without loss of consciousness,

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2.5 times greater for mTBI with loss of consciousness, and 3.8 times greater for more severe TBI. While the overall incidences are still small, they again point to the value of this CENC research and the need for individuals with TBI histories and their healthcare providers to be aware of this connection.4 Ongoing research by the CENC team includes identifying lifetime approaches to brain health and cognitive wellness (e.g., plant-based diet, daily exercise, stress reduction, high blood pressure treatment, weight loss, improved sleep patterns, managing mental illnesses, etc.). An exciting area of research is looking at fluid biomarkers to measure the health and recovery of the brain. One such biomarker is tau protein, which is found in the blood and saliva and, therefore, easily tested. In a healthy person, tau proteins normally help stabilize a part of brain cells called microtubules. However, in people with neurodegenerative disorders, like Alzheimer’s disease, tau proteins pull away from the microtubules and stick to each other, eventually forming filaments and tangles that disrupt communication between brain cells. Elevated levels of tau protein in the blood are indicative of declining brain health. Researchers conducted a study with 195 participants, average age of 40, from four CENC Veteran Affairs Medical Centers, and examined the tau protein levels in their blood plasma to determine if mTBI caused any change in those biomarker levels. Researchers noted there were no changes in tau protein levels in veterans who had 1–2 concussions as compared to veterans with no concussions, but tau levels were elevated for veterans who had experienced 3 or more concussions.5 This marker could identify patients at risk for neurodegenerative disorders in the future and help them seek preventative measures. Many of the CENC studies were pilot or proof of concept trials; researchers were testing the feasibility of the study or its hypothesis on a smaller population. The next phase of research involves clinical trials with a much larger patient population that will measure results over a longer period of time. That’s where the next phase of CENC begins. LONG-TERM IMPACT OF MILITARY-RELEVANT BRAIN INJURY CONSORTIUM (LIMBIC) This fall, VCU announced it received another $50 million federal grant to pursue the CENC research and further study the long-term impacts of concussions on service members and veterans. This ongoing study is called the Long-term Impact of Military-relevant Brain Injury Consortium (LIMBIC). Dr. Cifu will continue as the principal investigator. “We’ve narrowed the focus from 11 studies to 2 major, multi-tiered epidemiologic studies,” said Dr. Cifu. “The first study will increase our longitudinal cohort of 1,700

THE PERSONAL TOUCH

Helping Out Our Future Military Brothers and Sisters “I knew something bad had happened, but being deployed you just keep driving on,” U.S. Army veteran Joe Montanari told us. “I didn’t even know I had experienced a concussion until I started working with CENC.” Joe proudly served as a weapons specialist in the U.S. Army from 1999 to 2008, deployed to locations in Germany, Kosovo and Iraq. He was medically discharged after six years of active duty and four years in the National Guard. “In talking with my friends, a few of us returned home with the same symptoms — headaches like crazy, not sleeping at all and lightheadedness. Your balance really goes sometimes — it’s like standing in a parking garage on the rubber joints when a car goes by and you can feel the shakiness and instability for a couple seconds,” Joe explained. Joe is currently serving as a CENC military coordinator, where he is responsible for both recruiting and retaining service members and veterans as participants in the LIMBIC-CENC longitudinal study. He is also a participant in this research study. For him and veterans like him, it’s not just about returning home, it’s working hard to return to the fullest capacity possible to be there for their families. It was through his training and participation with CENC that he learned he was experiencing postconcussion symptoms from two combat-related mild traumatic brain injuries. “I’m the type of person that if something happens with my health, I like to break

Joe Montanari is pictured in 2002 during his military service as a U.S. Army weapons specialist. Photos: Courtesy of Joe Montanari

Joe Montanari returns home to his wife Micah following his first deployment to Iraq in 2005.

it down and know what’s going on so I can get the right treatment. Knowledge is empowering.” Joe also hopes to be of service and use his experience to help future military service members. “I’ve already been through everything and experienced the injuries, so if I can help someone else out, I’m all about that. I know a lot of people I’ve talked to feel the same way. It’s just helping out a future brother or sister who might sustain a mild traumatic brain injury in combat.” If you’re a veteran or service member interested in speaking with Joe to learn more about the LIMBIC-CENC research or become a study participant, please email him at joseph.montanari@vcuhealth.org.

Joe Montanari, a U.S. Army veteran who suffered a traumatic brain injury while serving in Iraq, not only works as a military coordinator for the CENC and LIMBIC research grants but is also engaged as a study participant. Photo: Julia Rendleman, VCU University Marketing

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LIMBIC Sites Cores Coordinating Center – Virginia Commonwealth University, Richmond, VA Imaging Core – VA Salt Lake City Health Care System/University of Utah, Salt Lake City, UT Clinical Studies Core – Virginia Commonwealth University, Richmond, VA Biomarkers Core – Uniformed Services University of the Health Sciences/National Institutes of Health, Bethesda, MD Data Management Biostatical Core – Hunter Holmes McGuire VA/Virginia Commonwealth University, Richmond, VA – VA Salt Lake City Health Care System/University of Utah, Salt Lake City, UT

OR ID

VT NH WI

NY MI

San Diego Area

SC AL

Maryland

NJ MD DE

MS TX

OH WV

MA CT RI

D.C. Virginia

LA FL

Tampa Bay Area

Studies Prospective Longitudinal Study Enrollment Sites – Hunter Holmes McGuire VA, Richmond, VA – James A. Haley Veterans Hospital, Tampa, FL – VA Boston Healthcare System, Boston, MA – VA Portland Health Care System, Portland, OR – Michael E. DeBakey VA Medical Center, Houston, TX – South Texas Veterans Healthcare Center, San Antonio, TX – WG Hefner VA Medical Center, Salisbury, NC – Minneapolis VA Health Care System, Minneapolis, MN – Eisenhower Army Medical Center, Fort Gordon, GA – Fort Belvoir Community Hospital, Alexandria, VA – VA San Diego Health System/University of California/Camp Pendleton, San Diego, CA

Prospective Longitudinal Recruiting Sites – MacDill Air Force Base, FL – Joint Base Lewis-McChord, WA – Fort Stewart, GA – Fort Jackson, Columbia, SC – Naval Amphibious Base Coronado, Coronado, CA Retrospective Study Sites – San Francisco VA Medical Center/University of CaliforniaSan Francisco – VA Palo Alto Health Care Systems/Stanford University – University of Utah/VA Salt Lake City Health Care System

veterans and service members to more than 3,000 from all eras of military combat (Vietnam to the present). Approximately 80% of this group will have experienced at least one mTBI, while the remaining 20% will be the control group who were exposed to combat but didn’t have a concussion. Participants from both groups are likely to have other common conditions associated with combat, such as PTSD, depression, chronic pain and anxiety. The control group will allow us to see what’s caused by having been exposed to the combat setting versus what’s attributable to the additional mTBI. “As with the research started in CENC, we’ll be getting a 360-degree overview of every possible aspect of these participants, from their brain and nervous systems, to their endocrine and cardiovascular systems. We’ll continue to follow this group annually over the course of their lives to search for any evidence of decline in function, including dementia and Parkinson’s disease.” The second set of LIMBIC studies will expand the use of the CENC mega-database of more than 2 million veterans and service members to look for further associations and relationships that can then be crossvalidated in the longitudinal study. Researchers will use this massive dataset to investigate whether mTBI is linked to higher incidences of dementia, Parkinson’s disease, depression, opioid use, chronic pain, PTSD or suicide risk. “We have initial analyses revealing that significant trends can be seen in these mega-data supporting the

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Coordinating Center Research Core Prospective Longitudinal Study Enrollment Site Prospective Longitudinal Recruiting Site Retrospective Study Site

linkage between higher rates of these conditions in veterans and service members with mTBI,” Dr. Cifu explained. “We’re going to apply what we learn from this massive database to the ongoing longitudinal study of more than 3,000 participants. We’ll be able to see if we find these problems occurring at the individual level, better analyze their causes and then apply clinical trials as cutting-edge treatments to help members of this group. It’s all about translating findings from big data to longitudinal data so that actual preventative and treatment interventions can be applied in real-time.” Over the next five years, the LIMBIC longitudinal study will include multiple intervention trials to examine treatments for common issues associated with combatrelated mTBI, including headaches, insomnia, PTSD and memory issues. “As clinicians, we want to take the theoretical and apply it to our patients and help them get well and improve the quality of their lives, as well as reduce their risk for problems in the future. Knowing the future risks enables us to take bold steps now to maintain wellness,” said Dr. Cifu. The research findings of LIMBIC-CENC will also be applicable to nonmilitary members of the general public. According to the CDC, in 2014 there were approximately 2.5 million TBI-related visits to emergency departments across the U.S. The most common injuries were falls, especially in older adults, motor vehicle accidents and sports-related injuries.6

LOVING YOUR BRAIN For veterans, service members, athletes and anyone who has suffered a concussion or even multiple concussions, Dr. Cifu has a positive message. “Concussions and related injury factors contribute to less than 1% of all dementia and ‘bad genes’ may add another 5–8% at most. On the other hand, at least 50% of all dementias are the result of common lifestyle factors that are within everyone’s control. Additionally, it’s not the one-time concussion that typically causes long-term issues, if it was treated appropriately,” Dr. Cifu explained. “People who have a concussion improve and can return to their lives 99% of the time with the right diagnoses and care, and it’s important to let them know that — YOU WILL GET WELL! For anyone who is still having ongoing symptoms, work with your primary care clinician to get additional information and care. The brain, the tissues around the neck and skull, and the other areas affected have remarkable abilities to heal and adapt, and you can be taught to control your symptoms and enjoy your lives. “Our LIMBIC-CENC team at VCU and the McGuire VAMC (and nationwide) want to take this opportunity to educate people (injured individuals, their loved ones, clinicians) how to ‘love’ and nurture their brains and take care of their overall health over the long-term. “Eating a vegetable-based diet, getting the right amount of sleep, finding a form of exercise that you enjoy and will do consistently, managing your weight and blood pressure, having good social support, keeping your mind active and engaging in a spiritual practice — these are the most important ways to support your whole health and offer your brain optimal wellness as you age. “I’d like to acknowledge all the amazing researchers who are diligently working across the country, and most

importantly, I’d like to thank our military veterans and service members who have risked their lives and sacrificed so much and are now helping us by participating in these studies,” said Dr. Cifu. If you would like to read more about the LIMBIC-CENC studies, please visit www.cencstudy.org. If you would like to support traumatic brain injury research at VCU Health, please contact Brian Thomas, MCV Foundation vice president and chief development officer, at 804-828-0067 or brian.thomas@vcuhealth.org.

1. According to the Defense and Veterans Brain Injury Center for the time period 2000–2018 Q1: https://dvbic.dcoe.mil/dod-worldwide-numbers-tbi. 2. William C. Walker, Kayla J. Nowak, Kimbra Kenney, Laura Manning Franke, Blessen C. Eapen, Karen Skop, Harvey Levin, Amma A. Agyemang, David F. Tate, Elisabeth A. Wilde, Sidney Hinds & Tracy L. Nolen (2018). Is balance performance reduced after mild traumatic brain injury? Interim analysis from chronic effects of neurotrauma consortium (CENC) multi-centre study, Brain Injury, 32:10, 1156-1168, doi: 10.1080/02699052.2018.1483529. 3. Raquel C. Gardner, Amy L. Byers, Deborah E. Barnes, Yixia Li, W. John Boscardin, Kristine Yaffe. Mild TBI and risk of Parkinson disease: A Chronic Effects of Neurotrauma Consortium Study. Neurology. 2018;90(20):e1771-e1779. doi:10.1212/WNL.0000000000005522. 4. Deborah E. Barnes, Amy L. Byers, Raquel C. Gardner, Karen H. Seal, W. John Boscardin, Kristine Yaffe. Association of Mild Traumatic Brain Injury With and Without Loss of Consciousness With Dementia in U.S. Military Veterans. JAMA Neurol. 2018;75(9):1055-1061. doi:10.1001/jamaneurol.2018.0815. 5. Kimbra Kenney, Bao-Xi Qu, Chen Lai, Christina Devoto, Vida Motamedi, William C. Walker, Harvey S. Levin, Tracy Nolen, Elisabeth A. Wilde, Ramon Diaz-Arrastia, Jessica Gill and the CENC Multisite Observational Study Investigators. Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury. Brain Injury. June 2018;32(10):1276-1284. doi:10.1080/02699052.2018.1483530. 6. According to the Centers for Disease Control and Prevention: www.cdc.gov/ traumaticbraininjury/data/tbi-ed-visits.html.

U.S. Army Veterans (left and right) Kevin Sickinger and Joe Montanari work with Dr. Cifu (center) at the Hunter Holmes McGuire VA Medical Center to recruit LIMBIC research participants. Photo: Julia Rendleman, VCU University Marketing

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FACULTY SPOTLIGHT

GOOD VIBRATIONS

Treating Symptoms of Parkinson’s Disease By Eric Peters

INGRID PRETZER-ABOFF, PH.D., RN Associate Professor, Senior Nurse Researcher Department of Adult Health and Nursing Systems VCU School of Nursing

Last year, Ingrid Pretzer-Aboff, Ph.D., RN, and several VCU colleagues received a $434,715 grant from The Michael J. Fox Foundation to study a vibrating device worn inside the shoe that could significantly reduce or put an end to a symptom of Parkinson’s disease known as freezing of gait. This symptom, which nearly 60% of people with Parkinson’s disease experience, manifests in a complete stop or prolonged shuffle in the feet or legs despite an individual’s best intentions to move forward. No medications or surgeries currently are available to treat it. Dr. Pretzer-Aboff and Leslie Cloud, M.D., neurologist at the VCU Health Parkinson’s and Movement Disorders Center, are leading a team of five VCU researchers in a two-year randomized controlled clinical trial to assess the best therapeutic dose and duration of vibration to reduce the occurrence and severity of the freeze. Dr. Pretzer-Aboff has studied vibration therapy in Parkinson’s patients for 10 years. Her research focuses on developing interventions that improve function and optimize the independence of people with Parkinson’s disease. She is a member of the Movement Disorder Society, Gerontological Society of America, American Geriatric Society, Sigma Theta Tau and the Virginia Nurses Association. How does freezing of gait affect people with Parkinson’s disease physically and emotionally? Freezing of gait is a problem described by patients as the feeling of their feet being glued to the floor. During a freeze, they are unable to walk in a normal heel to toe fashion and cannot move forward. Episodes can last seconds or minutes and are often triggered when initiating In a lab at the VCU School of Nursing, Ingrid Pretzer-Aboff, Ph.D., RN, studies a vibrating device worn inside the shoe (see top of facing page) that could significantly reduce or put an end to a symptom of Parkinson’s disease known as freezing of gait. Dr. Pretzer-Aboff’s research is supported by The Michael J. Fox Foundation. Photos: Kevin Schindler

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“Countless people with Parkinson’s disease I have met through my research have looked me straight in the eyes and said, ‘Thank you for helping us.’”

Ingrid Pretzer-Aboff, Ph.D., RN

walking or by the person’s physical surroundings, such as cluttered spaces or small doorways. Even the time pressure of having to enter or exit an elevator before the doors close can trigger a freeze. People with freezing of gait are also at risk for falls. As one can imagine, it can be quite difficult for a person experiencing freezing of gait to freely move in their homes and in community settings as they once did. For some, it can be quite isolating as they end up staying home rather than risk freezing in public or falling. Patients experience stress and often depression as they lose their independence and rely on family and friends for assistance. Is using vibration therapy to help people with Parkinson’s disease and freezing of gait a new concept? No, the use of vibration to help people with Parkinson’s disease is not a new concept. About 200 years ago, Dr. Jean-Martin Charcot invented a vibrating chair. As a neurologist and scientist, he was curious of the effect it would have on his patients who suffered from neurological disease. This included people with Parkinson’s disease. It was reported at the time that people with Parkinson’s disease seemed to “walk more freely” after being on the chair. Over the years, various people studied vibration’s effect on Parkinson’s patients and it was anecdotally and empirically noted that there was an improvement in several symptoms. However, no one has taken the concept as far as we have. That is, we are seeking to answer whether there is a specific dose of vibration frequency, amplitude and duration of treatment that optimizes gait of people with Parkinson’s disease. What is it about your research that motivates you each day? For the last three decades, I have worked with people with Parkinson’s disease and their family members in acute care, community and research settings. I have met many people

living with Parkinson’s disease who, despite all the difficulties they experience, can still tell a good joke, share their experiences, teach others about this puzzling disease and remain grateful for help they get from their families, friends and healthcare providers. Countless people with Parkinson’s disease I have met through my research have looked me straight in the eyes and said, “Thank you for helping us.” I am motivated every day by the patients I work with to try to help them deal with their disease. Why is the MCV Campus at VCU Health a good place for you to conduct your research? I moved here a little over two years ago and I honestly feel like I found the perfect place to conduct my research and move it forward. The MCV Campus and VCU Health collectively have a culture that supports innovative research, new ideas and collaborative work. The wealth of knowledge, resources and talent here support the many facets of my current research and future ideas for projects. I work closely with Dr. Leslie Cloud and her research staff in the Department of Neurology, Dr. R.K. Elswick Jr., research faculty and staff at the School of Nursing, and students across campus. I recently received a VCU School of Nursing Innovation Grant that supports work with Hawa Stwodah in the School of the Arts’ Department of Fashion Design and Merchandising for a project to design a sock-like wearable device designed to incorporate the vibration technology. I am excited to be here at VCU as the research infrastructure is outstanding and opportunities for collaboration are infinite! If you are interested in supporting Dr. Pretzer-Aboff’s work with Parkinson’s disease or strengthening the infrastructure that nurtures lifesaving research at VCU Health, please contact Pamela Lowe, senior director of development at VCU School of Nursing, at 804-827-0020 or plowe@vcu.edu.

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Scents and Sense Ability By Paul Brockwell Jr.

Two researchers’ novel application of technology passes the smell test for restoring olfactory function. Imagine, for a moment, never enjoying your favorite smells again — gone are the aromas of fresh-baked cookies, clean sheets or a favorite scented candle. Gone too is the ability to enjoy the flavor of favorite foods and drinks. And the ability to recall cherished memories so closely linked to smell vanishes without a trace. This condition — the complete loss of a person’s sense of smell — is called anosmia. Researchers have found it challenging to know how many people are affected by it. Grant funding for more thorough assessment and study of the condition has been scarce, but the most current studies estimate around 3.4 million people, or 3.2% of the general U.S. adult population, suffer from complete or severe loss of smell.1 The problem’s scope receives less attention than vision and hearing disorders, but anosmia has an unseen cost. Losing olfactory system function can dramatically affect a person’s quality of life. People report an inability to enjoy food and flavors. Anosmia patients also face significant lifelong safety risks when they can no longer detect threats, such as gas leaks or spoiled food. No treatment currently exists to restore the loss of smell caused by severing of the olfactory nerves. That’s been a nagging problem for Richard M. Costanzo, Ph.D., professor emeritus and director of the Smell and Taste Disorders Center in the VCU Health Department of Otolaryngology — Head and Neck Surgery. The clinic is one of the few of its kind in the country, and rarely a week goes by that Dr. Costanzo doesn’t hear from another person seeking help. Dr. Costanzo’s lab investigates methods to promote regeneration and repair of the olfactory system, and his research focuses on the unique ability of the olfactory system for neurogenesis and replacement of degenerating neurons. That singular ability, however, is unable to compensate for the loss of smell that results from severing nerves from the olfactory bulb. EXISTING TECHNOLOGY MEETS AN UNSOLVED PROBLEM Since Dr. Costanzo arrived at VCU in 1979, he’s been trying to develop a clinical solution for patients experiencing the complete, neuronal-based loss of smell. The condition is common in people who have experienced head trauma, when temporary displacement of the brain can sever connections between neurons in the nose and the olfactory bulb. Recent

advances in understanding how the olfactory system functions and can be mapped provided him with the inspiration to continue searching for a solution. Dr. Costanzo said he was envious of what could be done for hearing loss by colleagues like Daniel M. Coelho, M.D., Douglas Hayden Professor of Otology, Neurotology and Skull Base Surgery and director of the Cochlear Implant Center at VCU Health. Dr. Coelho has expertise in cochlear implants, the complex devices that bypass damage to the normal hearing process in order to directly stimulate the auditory nerve with electrical signals that provide a sense of hearing to individuals with severe hearing loss. “I’ve been searching my whole career for a way to help people with loss of smell, and not so far away in the human head is another sense with a wild success story,” Dr. Costanzo said. “I thought, it’s too bad we can’t do that. Dan and I were talking one day, and he told me, ‘You know with hearing we use a strategy where we can bypass the damage and stimulate the nervous system and restore hearing, so why can’t we do that for a sense of smell?’” Their idea sent the two doctors on a promising path and led to a research partnership both describe as fortuitous, given their respective expertise. They received funding from the MEDARVA Foundation that was critical for their early stage research. The grant helped keep the research project alive, enabling Drs. Coelho and Costanzo to establish proof of concept on a high-risk venture. “If that hadn’t happened, the idea would likely be buried like so many others,” Dr. Costanzo said. The progress made possible by the MEDARVA grant inspired private giving from Scott Moorehead (see page 35), an Indiana-based entrepreneur who suffers from anosmia. This type of support for basic science research was crucial because federal funding is increasingly more challenging to secure for untested ideas related to olfaction. ESTABLISHING PROOF OF CONCEPT The team conducted two studies that tested their theories about creating smell perceptions using electrical stimulation of the olfactory bulb. Their first experiment confirmed that different odors produced different neural activity within the olfactory bulb. They recorded the neural response patterns to various odor stimulants with a 32-electrode array connected to a monitoring system. Data from their study

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Olfactory System

This illustration shows how an intact olfactory system would function. In patients with anosmia, or the complete loss of smell, the nerve connections to the olfactory bulb (inset) are severed when injuries shift the brain and shear the nerve connections to the olfactory bulb, which run through delicate, spongy bone known as the cribriform plate. Illustration: Jacopin / BSIP / Science Photo Library

indicated that different odors result in localized response patterns within the olfactory bulb. In 2016, they published findings from these efforts to spatially map the olfactory bulb through both odor presentation and direct electrical stimulation of olfactory systems.2 A second study, published in 2018, confirmed that direct stimulation of the olfactory bulb created spatial patterns of neural activity similar to those observed during normal, functioning olfaction.3 Both studies supported the theory behind using electrical stimulation for treatment of anosmia. Their basic research has produced important discoveries. While the idea of restoring a sense of smell through electrical stimulation poses technical hurdles, the studies suggest that unique perceptions can be achieved by using the same principles of highly focused patterns of electrical stimulation to the olfactory bulb. Additionally, the use of different current and time intervals may, similar to the development of cochlear implants for hearing loss, be critical for refining the perception. Eric Holbrook, M.D., an associate professor of otolaryngology at Harvard Medical School, completed

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an NIH fellowship in Dr. Costanzo’s lab prior to his residency at VCU Health. In 2018, he and his team published a report on their success in using electrical stimulation to create a smell sensation in a small study of five human subjects. In this study, the subjects were screened to confirm their ability to smell. Each participant was already undergoing a nasal endoscopy, which enabled Dr. Holbrook to insert electrodes at three areas along the thinnest part of the cribriform plate and to induce anosmia with topical anesthesia. The study participants were then exposed to electrical stimulation of the olfactory bulb to see if they could perceive smell while current was stimulating the olfactory bulb. Three people reported the sensation of an odor with the electrical stimulus. None could specify what kind of smell they experienced, but one participant described it as an “onion-like smell.” All participants tolerated the study with minimal discomfort.4 “That’s really important — to be able to confirm and really drive Dan and Rich’s research forward and even get more interest in this concept of artificially stimulating the olfactory bulb through the use of electricity and preparing for the use of implants to have some chance for restoring sense of smell,” Dr. Holbrook said. Dr. Holbrook hopes that other scientists and industry leaders will see this line of inquiry as a viable future treatment option for anosmia. “We’ve been many years without breakthroughs in restoring smell,” he said. “It’s going to take a lot of work still, but we need to search this avenue of potential therapies for people with smell loss.” MAKING FUTURE SENSE After establishing proof of concept, Drs. Coelho and Costanzo are continuing their research on smell restoration and have partnered with the university’s office of research and innovation to navigate the path from invention disclosure to a patent-protected technology. “Over the past several years, VCU Innovation Gateway has helped transform the treatment of anosmia from the theoretical to the possible,” Dr. Coelho said. The prototypes they developed use the same technology behind cochlear implants, with both external sensors and internal processors, and Drs. Coelho and Costanzo are cautiously optimistic about the direction of their project. Now they are refining sensors on prototypes and thinking through the design of surgical protocols that will ensure patient safety and effectiveness with the device. They are heartened by the response of one survey of anosmia patients. Of those surveyed, nearly 30% of respondents expressed willingness to undergo head surgery to correct their smell disorder.5 That sentiment is encouraging as they

work to create a device and surgical method that could be either minimally or significantly invasive. The patent contains novel methods for gas sensing technology that would aid in detection of different odors. “That technology still needs some further development,” Dr. Costanzo said. “But we can start with some basic detections and simple discriminations. And Dan was explaining to me that when they first started cochlear implants it was a similar path.” It is true that early cochlear implant developments provided not the perfect fidelity of sound, but the ability to detect sound. Similarly, they are realistic about what to expect as their research continues. The olfactory system is more sensitive and more complicated than hearing and even vision. The human nose can distinguish around 1 trillion different odors according to research in the journal Science.6 However, the ability to fine-tune a device to that level of discrimination may not be necessary. For example, the scent of a rose can include up to 275 unique

odorants, but only a small fraction of them may be required for a person without congenital anosmia to identify what they’re smelling. The initial aim for Drs. Coehlo and Costanzo is not to achieve perfect detection of certain scents, but they are not shy to say they hope that ultimately may be possible. “Our first goal is to achieve some sort of smell perception,” Dr. Coelho said. “We’re currently planning human pilot studies that will further our proof of concept.” Dr. Coelho and Dr. Costanzo have built partnerships with collaborators at medical device manufacturing companies who provided some of their cochlear implant components for modification. They are working with other Harvard-based surgeons, including Dr. Holbrook, to develop and refine surgical protocols for the first in-human applications. What remains most exciting to them is how this effort to develop smell restoration technology has been a collaborative, grassroots initiative originating here at VCU Health. Through their partnership, both Dr. Coelho

A sensational partnership was forged when Richard M. Costanzo, Ph.D. (right), professor emeritus and director of the Smell and Taste Disorders Center in the VCU Health Department of Otolaryngology, began working with Daniel Coelho, M.D., professor of otolaryngology and director of the VCU Health Cochlear Implant Center, to develop proof of concept for their theories on how to restore complete neuronal smell loss through electrical stimulation. Photo: Karl Steinbrenner

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The Early Prototype: This illustration models how the smell restoration device designed by Richard Costanzo, Ph.D., and Daniel Coelho, M.D., would function. The device includes sensors to detect odor particles and processors that would send electrical current to directly stimulate the brain’s olfactory bulb and create a sensation of smell.

How It Works: 1. The external sensors detect odors.

2. Signals from the sensor transmit to the external processor to be coded.

4 6 5

1 2

3. The external processor sends a unique code (based on the odorants) to the transmitter. 4. The transmitter sends the signal wirelessly across the scalp to the internal receiver-stimulator. 5. The internal receiver-stimulator sends the signal through a wire to the electrode array on the olfactory bulb. 6. The olfactory bulb is stimulated with a unique pattern based on the original odor. 7. Brain perceives a sense of smell.

Illustration: Tom Edwards

and Dr. Costanzo have made real progress toward a solution for this problem that effects millions. “We’ve invented something that can help people in the next 5–10 years,” Dr. Coelho said. “Our challenge now is more practical. Our idea applies existing technology, but what’s novel about what we’re doing is modifying it for this particular application.” The two wrote in one recently published article that “Although there is much to be done before an ‘olfactory implant’ is available, the present

findings lay the foundation for a novel method for treating anosmia, and in doing so, offer hope to those who suffer from the condition.”2

1. Howard J. Hoffman, Shristi Rawal, Chuang-Ming Li, and Valerie B. Duffy. New chemosensory component in the U.S. National Health and Nutrition Examination Survey (NHANES): First year results for measured olfactory dysfunction. Reviews in Endocrine and Metabolic Disorders. 17(2): 221-240. (2016).

4. Eric Holbrook, Sidharth V. Puram, et al. Induction of smell through transethmoid electrical stimulation of the olfactory bulb. International Forum of Allergy and Rhinology. DOI: 10.1002/alr.22237 (2018).

2. Daniel Coelho and Richard Costanzo. Spatial Mapping in the Rat Olfactory Bulb by Odor and Direct Electrical Stimulation. Otolaryngology – Head and Neck Surgery. DOI: 10.1177/0194599816646358 (2016). 3. Daniel Coelho and Richard Costanzo. Activation of the rat olfactory bulb by direct ventral stimulation after nerve transection. International Forum of Allergy and Rhinology. DOI: 10.1002/alr.22133 (2018).

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If you would like to contribute to Dr. Coelho’s and Dr. Costanzo’s research to develop smell restoration technology, please contact Brian Thomas, vice president and chief development officer at the MCV Foundation, at 804-828-0067 or brian.thomas@vcuhealth.org.

5. Gerold Besser, David T. Liu et al. Olfactory implant: Demand for a future treatment option in patients with olfactory dysfunction. Laryngoscope. Epub 2018/08/27. doi: 10.1002/lary.27476. (2018). 6. Caroline Bushdid, Marcelo Magnasco, Leslie B. Vosshall, and A. Keller. Humans can discriminate more than 1 trillion olfactory stimuli. Science. 343,1370–1372. DOI: 10.1126/science.1249168 (2014).

THE PERSONAL TOUCH

This illustration of their prototype shows how smell restoration sensors would detect, process, and stimulate the olfactory bulb Scott Moorehead was teaching his 6-year-old son how in order to restore a sense of smell. Sensors attached to glasses to skateboard their driveway when his feet slipped, detect odor particles and relay in information to a processor, which would signal an implanted device to deliver electrical current to and he went hurtling down toward the pavement. the olfactory bulb. The next stage of research involves refining an instant, a touching father-son moment turned surgery protocolsWithin and implant prototypes developed by Richard M. Costanzo, Ph.D., professor emeritus and director of the into an emergency. The back of Scott’s head absorbed the Smell and Taste Disorders Center in the VCU Health Department brunt of the impact when he hit the driveway, and his injuries of Otolaryngology and Daniel Coelho, M.D., professor of severe — fourImplant contiguous fractures otolaryngologywere and director ofhe thesustained VCU Cochlear Program. Illustration by Tom Edwards on his skull, two subdural hematomas and a massive

concussion. The rural hospital near his house had to airlift him to Fort Wayne, Indiana, for advanced trauma care. Scott remembers feeling loopy, annoyed and confused by a frequent question in the days following his accident. The staff were often checking on him and asking if he could smell. At the time, he insisted that he could, but at some point he realized he had, in fact, lost his ability to smell. Anosmia and other smell-related disorders are common in patients who suffer traumatic brain injuries. Some patients may recover the ability to smell over time as neurons regenerate and reconnect to the olfactory bulb. Unfortunately for Scott, his accident had severed the neural pathways and robbed him of this ability. The next few years were challenging for him, he said. Without any treatment options to restore his sense of olfaction, Scott had to adjust to life with an invisible injury that had ended his ability to enjoy the things he loved most. The first thing Scott noticed was how losing his sense of smell affected his quality of life, particularly enjoying food and flavor. The experience of taste comes from two different sources — the tongue, which can distinguish between temperature and four basic areas: sweet, sour, spicy or salty; and the olfactory system. What people often describe as flavor originates primarily from aromas detected by the olfactory nerves and the nearly 1 trillion unique odors that can be detected and sent to the brain.1

Dad and entrepreneur Scott Moorehead lost his sense of smell following a traumatic brain injury. His support of research by Drs. Costanzo and Coelho at VCU Health has helped move forward promising inquiries that aim to develop a device that can restore a sense of smell in patients like Scott who suffer from anosmia, or the complete loss of olfactory ability. Photo: Courtesy of Culture of Good

“If you blindfolded me and put six different ice cream flavors in front of me, I probably wouldn’t be able to tell the difference,” Scott said. “They’d all be cold and somewhat sweet. It’s super frustrating — how it impacts your taste — and that’s difficult to explain to a lot of people.” Safety is also a huge concern for people with anosmia. Without the ability to smell, individuals are unable to detect when there may be a gas leak or spoiled food. Scott recalls one terrifying moment when he was home alone and watching TV. His wife arrived home with their kids in tow, and she immediately rushed them out into the yard. When she found Scott inside the house, she quickly yelled at him to get outside because the house reeked of gas. Scott, without a sense of smell, had no way of knowing the tank for their propane fireplace had been steadily leaking gas

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“If you blindfolded me and put six different ice cream flavors in front of me, I probably wouldn’t be able to tell the difference. They’d all be cold and somewhat sweet.” into the house. The situation was a dangerous one that could have ended in tragedy. “That scared the crap out of me,” Scott remembered. “There was propane gas all over my house, and I had zero idea I was sitting in the middle of it.” Scott also struggled with the emotional weight of losing the sense of smell. In addition to worrying about personal hygiene, he remembers sleepless nights thinking about how his ability to recall major life moments and loved ones had been impaired and limited by his inability to smell. “It definitely had me in a funk,” Scott recalled. “I dealt with a lot of anxiety and stress. If I’m being honest with myself, I was probably borderline depressed.” Scott searched endlessly for a solution online and came up empty-handed. After encountering many similar stories, he eventually found peace with his condition, but never fully gave up his interest in the problem. “You just reconcile and say this wasn’t my choice. I’m going to move on,” Scott said. Several friends and colleagues pledged to alert Scott if they ever encountered anything that might lead to treatment for his anosmia. Years later, a colleague and friend discovered the work of Dr. Costanzo and Dr. Coelho at VCU Health and shared it with Scott. They were far enough along with patents and testing to intrigue him.

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Scott Moorehead “I’m an entrepreneur,” Scott explained. “I’m used to being my own boss and believe almost any problem can be solved with enough time, effort and money.” After touring their labs and meeting with the team investigating the restoration of smell through electrical stimulation at VCU Health, Scott found himself in a position to financially support their research at a crucial time to continue the lab’s work. “All of these things came into a collision — this miniature explosion happened in my brain in a good way this time,” Scott said. In part because of Scott’s support, the team at VCU Health was able to build off their research establishing proof of concept for a device to restore smell. And their work to develop technology that can restore a sense of smell in humans remains ongoing. “The scars that I have are pretty permanent,” Scott said. “If I could help somebody else not have to go through the same type of mental and physical anguish that I did, then that’s a huge win.” 1. Caroline Bushdid, Marcelo Magnasco, Leslie B. Vosshall, and A. Keller. Humans can discriminate more than 1 trillion olfactory stimuli. Science. 343,1370–1372. DOI: 10.1126/science.1249168 (2014).

NEXT is published by the MCV Foundation to share the latest breakthroughs occurring at VCU Health and the positive impact these exciting innovations have on our patients. MANAGING EDITOR:

Alex Henley ASSOCIATE EDITORS:

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Big River Advertising SCIENTIFIC ADVISORY PANEL:

Joseph T. DiPiro, Pharm.D. Alpha A. “Berry” Fowler III, M.D. Steven R. Grossman, M.D., Ph.D. F. Gerard Moeller, M.D. Jerome F. Strauss III, M.D., Ph.D. Wanchun Tang, M.D. The Medical College of Virginia Foundation was established in 1949 to inspire and steward philanthropic resources for our MCV Campus Partners at VCU Health. The MCV Foundation manages more than $600 million in assets to ensure VCU Health remains at the forefront of excellence and innovation in patient care, research and education as one of the top academic health centers on the East Coast. Through 1,700 funds, the MCV Foundation provides scholarships, professorships, research and program funds to support the lifesaving work occurring at VCU Health every day. The MCV Foundation’s campus partners include: VCU College of Health Professions, VCU School of Dentistry, VCU School of Medicine, VCU School of Nursing, VCU School of Pharmacy, VCU Massey Cancer Center and VCU Medical Center. To learn more, visit : www.mcvfoundation.org Please address comments or subscription requests to: Alex Henley MCV Foundation 1228 East Broad Street Box 980234 Richmond, VA 23298 alex.henley@vcuhealth.org

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